Stanford Advisors

All Publications

  • Near-Infrared IIb Fluorescence Imaging of Vascular Regeneration with Dynamic Tissue Perfusion Measurement and High Spatial Resolution ADVANCED FUNCTIONAL MATERIALS Ma, Z., Zhang, M., Yue, J., Alcazar, C., Zhong, Y., Doyle, T. C., Dai, H., Huang, N. F. 2018; 28 (36)
  • Bright quantum dots emitting at 1,600 nm in the NIR-IIb window for deep tissue fluorescence imaging. Proceedings of the National Academy of Sciences of the United States of America Zhang, M., Yue, J., Cui, R., Ma, Z., Wan, H., Wang, F., Zhu, S., Zhou, Y., Kuang, Y., Zhong, Y., Pang, D., Dai, H. 2018; 115 (26): 6590–95


    With suppressed photon scattering and diminished autofluorescence, in vivo fluorescence imaging in the 1,500- to 1,700-nm range of the near-IR (NIR) spectrum (NIR-IIb window) can afford high clarity and deep tissue penetration. However, there has been a lack of NIR-IIb fluorescent probes with sufficient brightness and aqueous stability. Here, we present a bright fluorescent probe emitting at 1,600 nm based on core/shell lead sulfide/cadmium sulfide (CdS) quantum dots (CSQDs) synthesized in organic phase. The CdS shell plays a critical role of protecting the lead sulfide (PbS) core from oxidation and retaining its bright fluorescence through the process of amphiphilic polymer coating and transferring to water needed for imparting aqueous stability and compatibility. The resulting CSQDs with a branched PEG outer layer exhibited a long blood circulation half-life of 7 hours and enabled through-skin, real-time imaging of blood flows in mouse vasculatures at an unprecedented 60 frames per second (fps) speed by detecting 1,600-nm fluorescence under 808-nm excitation. It also allowed through-skin in vivo confocal 3D imaging of tumor vasculatures in mice with an imaging depth of 1.2 mm. The PEG-CSQDs accumulated in tumor effectively through the enhanced permeation and retention effect, affording a high tumor-to-normal tissue ratio up to 32 owing to the bright 1,600-nm emission and nearly zero autofluorescence background resulting from a large 800-nm Stoke's shift. The aqueous-compatible CSQDs are excreted through the biliary pathway without causing obvious toxicity effects, suggesting a useful class of 1,600-nm emitting probes for biomedical research.

    View details for DOI 10.1073/pnas.1806153115

    View details for PubMedID 29891702

  • Molecular Cancer Imaging in the Second Near-Infrared Window Using a Renal-Excreted NIR-II Fluorophore-Peptide Probe ADVANCED MATERIALS Wang, W., Ma, Z., Zhu, S., Wan, H., Yue, J., Ma, H., Ma, R., Yang, Q., Wang, Z., Li, Q., Qian, Y., Yue, C., Wang, Y., Fan, L., Zhong, Y., Zhou, Y., Gao, H., Ruan, J., Hu, Z., Liang, Y., Dai, H. 2018; 30 (22): e1800106


    In vivo molecular imaging of tumors targeting a specific cancer cell marker is a promising strategy for cancer diagnosis and imaging guided surgery and therapy. While targeted imaging often relies on antibody-modified probes, peptides can afford targeting probes with small sizes, high penetrating ability, and rapid excretion. Recently, in vivo fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) shows promise in reaching sub-centimeter depth with microscale resolution. Here, a novel peptide (named CP) conjugated NIR-II fluorescent probe is reported for molecular tumor imaging targeting a tumor stem cell biomarker CD133. The click chemistry derived peptide-dye (CP-IRT dye) probe afforded efficient in vivo tumor targeting in mice with a high tumor-to-normal tissue signal ratio (T/NT > 8). Importantly, the CP-IRT probes are rapidly renal excreted (≈87% excretion within 6 h), in stark contrast to accumulation in the liver for typical antibody-dye probes. Further, with NIR-II emitting CP-IRT probes, urethra of mice can be imaged fluorescently for the first time noninvasively through intact tissue. The NIR-II fluorescent, CD133 targeting imaging probes are potentially useful for human use in the clinic for cancer diagnosis and therapy.

    View details for DOI 10.1002/adma.201800106

    View details for Web of Science ID 000434034100025

    View details for PubMedID 29682821

  • 3D NIR-II Molecular Imaging Distinguishes Targeted Organs with High-Performance NIR-II Bioconjugates ADVANCED MATERIALS Zhu, S., Herraiz, S., Yue, J., Zhang, M., Wan, H., Yang, Q., Ma, Z., Wang, Y., He, J., Antaris, A. L., Zhong, Y., Diao, S., Feng, Y., Zhou, Y., Yu, K., Hong, G., Liang, Y., Hsueh, A. J., Dai, H. 2018; 30 (13): e1705799


    Greatly reduced scattering in the second near-infrared (NIR-II) region (1000-1700 nm) opens up many new exciting avenues of bioimaging research, yet NIR-II fluorescence imaging is mostly implemented by using nontargeted fluorophores or wide-field imaging setups, limiting the signal-to-background ratio and imaging penetration depth due to poor specific binding and out-of-focus signals. A newly developed high-performance NIR-II bioconjugate enables targeted imaging of a specific organ in the living body with high quality. Combined with a home-built NIR-II confocal set-up, the enhanced imaging technique allows 900 µm-deep 3D organ imaging without tissue clearing techniques. Bioconjugation of two hormones to nonoverlapping NIR-II fluorophores facilitates two-color imaging of different receptors, demonstrating unprecedented multicolor live molecular imaging across the NIR-II window. This deep tissue imaging of specific receptors in live animals allows development of noninvasive molecular imaging of multifarious models of normal and neoplastic organs in vivo, beyond the traditional visible to NIR-I range. The developed NIR-II fluorescence microscopy will become a powerful imaging technique for deep tissue imaging without any physical sectioning or clearing treatment of the tissue.

    View details for DOI 10.1002/adma.201705799

    View details for Web of Science ID 000428793600012

    View details for PubMedID 29446156

    View details for PubMedCentralID PMC5931222

  • A bright organic NIR-II nanofluorophore for three-dimensional imaging into biological tissues NATURE COMMUNICATIONS Wan, H., Yue, J., Zhu, S., Uno, T., Zhang, X., Yang, Q., Yu, K., Hong, G., Wang, J., Li, L., Ma, Z., Gao, H., Zhong, Y., Su, J., Antaris, A. L., Xia, Y., Luo, J., Liang, Y., Dai, H. 2018; 9: 1171


    Fluorescence imaging of biological systems in the second near-infrared (NIR-II, 1000-1700 nm) window has shown promise of high spatial resolution, low background, and deep tissue penetration owing to low autofluorescence and suppressed scattering of long wavelength photons. Here we develop a bright organic nanofluorophore (named p-FE) for high-performance biological imaging in the NIR-II window. The bright NIR-II >1100 nm fluorescence emission from p-FE affords non-invasive in vivo tracking of blood flow in mouse brain vessels. Excitingly, p-FE enables one-photon based, three-dimensional (3D) confocal imaging of vasculatures in fixed mouse brain tissue with a layer-by-layer imaging depth up to ~1.3 mm and sub-10 µm high spatial resolution. We also perform in vivo two-color fluorescence imaging in the NIR-II window by utilizing p-FE as a vasculature imaging agent emitting between 1100 and 1300 nm and single-walled carbon nanotubes (CNTs) emitting above 1500 nm to highlight tumors in mice.

    View details for DOI 10.1038/s41467-018-03505-4

    View details for Web of Science ID 000427929200002

    View details for PubMedID 29563581

    View details for PubMedCentralID PMC5862886

  • Donor Engineering for NIR-II Molecular Fluorophores with Enhanced Fluorescent Performance JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Yang, Q., Hu, Z., Zhu, S., Ma, R., Ma, H., Ma, Z., Wan, H., Zhu, T., Jiang, Z., Liu, W., Jiao, L., Sun, H., Liang, Y., Dai, H. 2018; 140 (5): 1715–24


    Organic fluorophores have been widely used for biological imaging in the visible and the first near-infrared windows. However, their application in the second near-infrared window (NIR-II, 1000-1700 nm) is still limited mainly due to low fluorescence quantum yields (QYs). Here, we explore molecular engineering on the donor unit to develop high performance NIR-II fluorophores. The fluorophores are constructed by a shielding unit-donor(s)-acceptor-donor(s)-shielding unit structure. Thiophene is introduced as the second donor connected to the shielding unit, which can increase the conjugation length and red-shift the fluorescence emission. Alkyl thiophene is employed as the first donor connected to the acceptor unit. The bulky and hydrophobic alkyl thiophene donor affords larger distortion of the conjugated backbone and fewer interactions with water molecules compared to other donor units studied before. The molecular fluorophore IR-FTAP with octyl thiophene as the first donor and thiophene as the second donor exhibits fluorescence emission peaked at 1048 nm with a QY of 5.3% in aqueous solutions, one of the highest for molecular NIR-II fluorophore reported so far. Superior temporal and spatial resolutions have been demonstrated with IR-FTAP fluorophore for NIR-II imaging of the blood vessels of a mouse hindlimb.

    View details for DOI 10.1021/jacs.7b10334

    View details for Web of Science ID 000424851500024

    View details for PubMedID 29337545

  • Boosting the down-shifting luminescence of rare-earth nanocrystals for biological imaging beyond 1500 nm. Nature communications Zhong, Y., Ma, Z., Zhu, S., Yue, J., Zhang, M., Antaris, A. L., Yuan, J., Cui, R., Wan, H., Zhou, Y., Wang, W., Huang, N. F., Luo, J., Hu, Z., Dai, H. 2017; 8 (1): 737


    In vivo fluorescence imaging in the near-infrared region between 1500-1700 nm (NIR-IIb window) affords high spatial resolution, deep-tissue penetration, and diminished auto-fluorescence due to the suppressed scattering of long-wavelength photons and large fluorophore Stokes shifts. However, very few NIR-IIb fluorescent probes exist currently. Here, we report the synthesis of a down-conversion luminescent rare-earth nanocrystal with cerium doping (Er/Ce co-doped NaYbF4 nanocrystal core with an inert NaYF4 shell). Ce doping is found to suppress the up-conversion pathway while boosting down-conversion by ~9-fold to produce bright 1550 nm luminescence under 980 nm excitation. Optimization of the inert shell coating surrounding the core and hydrophilic surface functionalization minimize the luminescence quenching effect by water. The resulting biocompatible, bright 1550 nm emitting nanoparticles enable fast in vivo imaging of blood vasculature in the mouse brain and hindlimb in the NIR-IIb window with short exposure time of 20 ms for rare-earth based probes.Fluorescence imaging in the near-infrared window between 1500-1700 nm (NIR-IIb window) offers superior spatial resolution and tissue penetration depth, but few NIR-IIb probes exist. Here, the authors synthesize rare earth down-converting nanocrystals as promising fluorescent probes for in vivo imaging in this spectral region.

    View details for DOI 10.1038/s41467-017-00917-6

    View details for PubMedID 28963467

    View details for PubMedCentralID PMC5622117